ES2227710T3 - DERIVATIVES OF TIENILCICLOHEXANO FOR THE SYNTHESIS OF TIENILCICLOHEXILOS. - Google Patents

Abstract

PCT No. PCT/FR97/01382 Sec. 371 Date Jan. 19, 1999 Sec. 102(e) Date Jan. 19, 1999 PCT Filed Jul. 24, 1997 PCT Pub. No. WO98/03498 PCT Pub. Date Jan. 29, 1998Novel thienylcyclohexane derivatives of general formula (I), wherein R' is the 2-thienyl or 3-thienyl radical, R is the cyano radical or a radical of formula -C(O)A, and R2'' is a saturated or unsaturated optionally cyclic hydrocarbon radical, or an aryl radical, are disclosed. Methods for preparing said compounds, and the use thereof as novel industrial products for the synthesis of thienylcyclohexyl derivatives, are also disclosed.

Description

Thienylcyclohexane derivatives for synthesis of the thienylcyclohexyl.

The present invention relates to new thienylcyclohexane derivatives, procedures for their preparation and its use as new industrial products for the synthesis of thienylcyclohexylated derivatives, and more particularly of (thienyl-cyclohexyl) cyclic amines such as those described in Eur. J. Med. Chem. (1994) 29, 869-876.

The invention aims at compounds of general formula I

one

in racemic form, of diestereoisomers or enantiomers in the which:

R represents the cyano radical or -C (O) A in which A represents a radical of formula OR 1 or NR 2 R 3 in which R 1, R 2 and R 3 independently represent a hydrogen atom or a group alkyl optionally substituted with aryl;

R 'represents the radical 2-thienyl or 3-thienyl;

R '' represents an alkyl radical if any substituted with aryl or an aryl radical as well as the salts thereof compounds.

The term "alkyl" refers to an alkyl radical. linear or branched that includes 1 to 12 carbon atoms. From preferably, the term "alkyl" represents an alkyl radical that it has 1 to 6 linear or branched carbon atoms and in Particularly methyl, ethyl, propyl, isopropyl radicals, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, isopentyl, hexyl e isohexyl

The expression aryl represents a radical aromatic, consisting of a cycle or condensed cycles; every cycle may eventually contain one or more heteroatoms identical or different chosen from sulfur, nitrogen or oxygen. Examples of aryl radical are phenyl, naphthyl radicals, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidyl, benzothienyl, benzofuryl and indolyl.

The invention has more particularly for target compounds of general formula 1 as defined above, in which:

R represents the cyano radical; a radical of formula -C (O) A in which A represents a radical of formula OR 1 or NR 2 R 3, in which R 1, R 2 and R 3 independently represent a hydrogen atom, a alkyl radical containing from 1 to 6 carbon atoms and optionally substituted with phenyl;

R 'represents the radical 2-thienyl or 3-thienyl;

R '' represents an alkyl radical containing 1 to 6 carbon atoms and optionally substituted with phenyl, or a phenyl radical

More particularly, the invention has for target the products described below in the examples, in particular products that respond to formulas following:

- 2-methyl-1- (2-thienyl) -cyclohexane-carbonitrile;

- acid 2-methyl-1- (2-thienyl) -cyclohexane-carboxylic acid;

- 2-methyl-1- (2-thienyl) -cyclohexane-carboxylate of ethyl;

- 2-methyl-1- (2-thienyl) -cyclohexane-carboxamide;

- N - [α-methyl - ((S) -phenylmethyl)] 2-methyl-1- (2-thienyl) -cyclohexane- carboxamide;

- 2-methyl-1- (3-thienyl) -cyclohexane-carbonitrile;

- acid 2-methyl-1- (3-thienyl) -cyclohexane-carboxylic acid;

- 2-methyl-1- (3-thienyl) -cyclohexane-carboxamide;

- 2-ethyl-1- (2-thienyl) -cyclohexane-carbonitrile;

- 2-propyl-1- (2-thienyl) -cyclohexane-carbonitrile;

- 2-benzyl-1- (2-thienyl) -cyclohexane-carbonitrile;

- 2-phenyl-1- (2-thienyl) -cyclohexane-carbonitrile;

in racemic form, of diesteroisómeros or of enantiomers

The invention also aims at a preparation process of compounds of general formula 1 such as defined above in which R represents the radical cyano or a radical of the formula -C (O) A in which A represents a radical of formula OR1 or N2R3 such as is defined above, characterized in that it reacts a product of general formula 1

1R'CH_ {R}

in which R and R 'have the meanings indicated above, with a product of formula general 2

2

in which Y and Y 'represent, independently, removable groups and R '' has the significance indicated above, in an inert solvent, in the presence of a strong base, to give a product of formula I.

The use of starting compounds in form racemic lead to the obtaining of compounds of formula I in the form racemic The use of a compound of formula 2, in form (R) or (S), allows to obtain a compound of formula I in the form of a substantially pure enantiomer.

In the product of formula 2, Y and Y 'represent removable groups such as a halogen, and preferably an atom of chlorine, or an aryl or alkylsulfonate radical.

For the implementation of the procedure above, an inert solvent is used for the reaction as, for example, acetonitrile, dimethylacetamide or dimethylformamide, and preferably dimethylformamide, in the presence of a strong base. The strong base can be chosen among products such as alkyl lithium (such as a methyl-, n-butyl, or t-butyllithium) or one of its derivatives such as lithium diisopropylamide (LDA) or lithium hexamethyldisilazane (LiHMDS), an alkaline alcoholate (by example of methylate, ethylate, propylate, butylate, tert-butylate, isoamylate or tert-amylate) or an alkali metal hydroxide. He compound of formula 1 is then added to said solvent, in presence of a strong base, at a temperature between -80 ° C and room temperature, preferably between -20 ° C and 0 ° C. The compound of formula 2 is then added at a temperature between -10ºC and + 10ºC, preferably at a temperature slightly below 0 ° C. The reaction medium is reheated to  then at a temperature between 20 ° C and 65 ° C and Keep under stirring for 15 minutes at a few hours. The reaction can be followed for example by chromatography (thin layer, soda or liquid depending on the case). After the reaction, the solvent is partially removed under reduced pressure and the residue is treated with a mixture of water and non-miscible solvent with water to extract the reaction product.

The products of general formula 1 are commercial or can be obtained by classic methods known for the expert.

Products of general formula 2 can obtained, for example, either by reaction of a compound organometallic on valerolactone, or one of its derivatives, followed by a reduction after an appropriate replacement of hydroxy groups, either by reaction of an organometallic of formula R '' - M-Hal on a 4- (halogenoformyl) alkylbutyrate followed by a reduction after an appropriate substitution of groups hydroxy, either by reaction of an organometallic of formula R '' - M-Hal on the compound appropriate general formula Y- (CH 2) 4 -C (O) Hal followed by a reaction after an appropriate replacement of the hydroxy group, according to reaction scheme 1 below.

The organometallic compound as it is defined above can be an organomagnetic compound or a compound obtained by exchange between an organomagnesic and a metal halide such as, for example, a copper chloride, of manganese or other product known to the expert.

Reaction scheme I

3

The compounds of formula 2 can be obtained also according to reaction scheme 2 below, by formula ketone reduction R'C (O) (CH 2) 2 CH = CH in which R '' has the significance indicated above, then a substitution appropriate hydroxy group so formed, followed by transformation of the alkyne into corresponding alcohol and finally of the appropriate replacement of the hydroxy group thus formed.

The compounds of formula 2 in the form of substantially pure enantiomer, can be prepared according to this reaction scheme 2, for example, incorporating a stage Supplemental separation of alcohols of formula R'C (OH) (CH 2) 2 CH = CH in the form of enantiomer substantially pure, then the treatment of one of the alcohols for the formation of the corresponding compound 2, in the substantially pure form desired. In the event that the separation of alcohols in substantially pure form be difficult, the racemic alcohol can be transformed into another compound whose enantiomeric forms are more easily separable; by For example, the alcohol can be reacted with the anhydride phthalic, then separate the diestereoisomeric forms of phthalate so formed, and transform the phthalate, in the form of a diestereoisomer substantially pure, in the corresponding alcohol, in the form of substantially pure enantiomer, and finally treat this alcohol according to reaction scheme 2.

Reaction scheme 2

4

In these reaction schemes 1 and 2 Y, Y 'and R' ' they have the significance indicated above and Hal represents a halogen atom.

The compounds of general formula I as is defined above in which R represents the radical -NR 4 R 5, can be obtained from the compound of corresponding formula I in which R represents the radical -C (O) NR_ {2} R_ {3} under operating conditions Classics known to the expert.

The compounds of general formula I as is defined above in which R represents an acid function, amide or ester, can also be obtained directly or indirectly from the corresponding compound of formula I in which R represents the cyano radical, under conditions Classic operations known by the expert, according to the scheme Reaction 3 next.

Reaction scheme 3

5

The objective compounds of the invention can then obtain in racemic form from starting compounds in racemic form. They can also be obtained with a conformation cis or trans predominant between the R and R groups. '' The utilization of a compound of formula 2, in the form (R) or (S), allows to obtain a single enantiomer all along the synthetic chain. For other  part, at each stage of the chain, a resolution is possible Either chemical or enzymatic.

Enzymatic resolution in the state of compound of formula I in which R represents the nitrile function, amide or ester, it is possible with, for example, a nitrilase, a amide hydratase or acylase, or an esterase respectively. At In the case of the ester, the Pig Liver is preferably used Esterase

The chemical resolution can be made with a chiral amine in the state of the compound of formula I in which R It represents the acid function. The amine can be chosen from among chiral amines known to the expert. Preferably, it use quinine or a α-methyl-benzylamine. At case of resolution with quinine, the acid salt (+) crystallizes preferably. Obtaining the acid (-) can obtained by precipitation of its salt with the D (+) α-methyl-benzylamine. Of the In the same way, the resolution can be made in the state of compound of formula I in which R represents an amine function by the use of optically active acids, and preferably the tartaric acid or a derivative of tartaric acid such as di-O, O'-toluoyltartaric.

The compounds of general formula 1 in which R represents the amino radical, are precursors of the compounds of formula II

6

in which R 'and R' 'have the meanings indicated above and E1 and E2 are joined together and form with the nitrogen atom to which they are attached, a heterocycloalkyl or heterocycloalkenyl. The expression heterocycloalkyl or herocycloalkenyl designates a cycloalkyl, saturated or unsaturated, containing 3 to 5 carbon atoms and at less a heteroatom. This radical may contain several identical or different heteroatoms. Preferably, the heteroatoms are chosen from oxygen, sulfur or nitrogen. Examples of heterocycloalkyl or heterocycloalkenyl radicals are the pyrrolidinyl, imidazolidinyl, pyrrazolidinyl radicals, piperidyl, piperazinyl, morpholinyl, isothiazolidyl, thiazolidyl, isoxazolidyl, oxazolidyl and 1,2,3,6-tetrahydropyridyl.

Thus the compounds of general formula II can obtained by reacting on the compound of formula I corresponding in which R represents the amino radical, a compound of formula Hal-B-Hal in the which Hal represents a halogen atom and B a chain appropriate hydrocarbon of 3 to 8 carbon atoms, saturated or unsaturated, under classical operating conditions known to the expert. The compounds of the general formula Hal-B-Hal are commercial and can Obtained by classical methods known to the expert from of the corresponding diol of formula HO-B-OH.

The invention also aims at, as new industrial products, and especially as products new industrials destined to the preparation of the products of formula (I), the compounds of formula 2 as defined above, in racemic or enantiomer form substantially pure.

The following examples are present for Illustrate the above procedures.

Preparation one

(+/-) 1,5-hexanediol

In a 6 l reactor under nitrogen atmosphere, 560 ml of ethyl 4-acetylbutyrate were introduced then 2.8 l of toluene. In an addition vial, they were placed 980 ml of a solution with 15% by mass tetrahydrogen aluminate of lithium in a toluene / THF mixture, 1 / 2.4. The addition was made of tetrahydrogen aluminate in 2 hours leaving the temperature Increase progressively to reflux. It remained at reflux during 3 hours. The reactor was then cooled to a temperature below 15 ° C, then 110 ml of a 5% soda solution and 250 ml of another 15% soda solution. It was allowed to stir 15 minutes, then 1l of tert-butyl methyl ether (MTBE). Be stirred again 15 minutes, then filtered over 270 g of Clarcel It was washed with 2.8 L of MTBE and the whole was concentrated. the filtered. 360 g of a fairly thick oil were recovered  corresponding to the desired product (Rdt = 86%).

13 C NMR (CDCl 3): 21.7; 23.1; 32.1; 38.5; 61.7; 67.3.

Preparation 2

(+/-) 1,5-dichlorohexane

Preparation 2 a: from compound 3

In a three-mouth reactor of 3 l under nitrogen atmosphere, 352 g of 1,5-hexanediol was introduced after 1 l of toluene. With the help of a foundry ampoule, 660 ml of thionyl chloride was added under good stirring in a 2 hour manner so that a regular gas evolution was obtained and the temperature below 40 ° C was preserved. It was then progressively refluxed and allowed to stir 1.5 hours. The excess thionyl chloride was then distilled until the temperature of the vapors reached 109 ° C. A volume of toluene equal to the distilled volume was then added and some milliliters were redistilled controlling that the temperature of the vapors was always 109-110 ° C. It was then cooled to 20-25 ° C and 500 ml of water was added dropwise. It was allowed to stir 15 minutes after the two phases were decanted. The organic phase was then washed 3 times with 400 ml of an aqueous saturated sodium bicarbonate solution (pH = 7) and with 500 ml of an aqueous saturated sodium chloride solution. Toluene was removed by concentration of the medium, then the oil obtained was distilled under vacuum. After removal of a 25 g head (Eb 3.75 = 39-54 ° C), 292 g of an oil corresponding to the desired product was recovered
(Eb 3.75 = 55-56 ° C).

13 C NMR (CDCl 3): 23.9; 25.2; 31.9; 39.4; 44.6; 58.3.

Preparation 2b: from compound 7

Working in the same way as in preparations 12, 13 and 14 below and starting from chloride methyl magnesium, the desired compound was obtained. The analytical characteristics are identical to those of the product obtained from preparation 2a.

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Preparation 3

Methyl 5-oxooctanoate

In a 250 ml reactor under the atmosphere of nitrogen, 2.82 g of magnesium was introduced. It was coated with THF and 1 ml of 1-bromopropane was poured. When the reaction started, a solution of 9.9 ml was added dropwise of 1-bromopropane in 150 ml of THF in 1.5 hours. After the addition was finished, it was allowed to stir 10 minutes, then it was taken at reflux for 3 hours. The medium was then cooled to -80 ° C, then a solution of 17 ml of 4- (methyl chloroformyl) -butyrate very slowly in 45 minutes. It was then stirred 1 hour at -70 ° C, then left return very slowly at 18 ° C (17 hours). The medium was treated reagent to add 160 ml of a saturated aqueous solution of ammonium chloride. It was stirred 30 minutes, decanted and re-extracted the aqueous phase with 100 ml of ether. The organic phases The residue was recovered in 200 ml of ether, then washed twice with 100 ml of water. It was dried over sulfate magnesium and concentrated with rotary evaporator. They were obtained like this 20.2 g of an oil that corresponds to the expected product.

13 C NMR (CDCl 3): 13.5; 17.1; 18.7; 32.8; 41.2; 44.5; 51.3; 173.4; 210.1.

Preparation 4

Methyl 5-oxoheptanoate

Working in the same way as in the Preparation 3, and starting from 4.5 ml of bromoethane, were obtained 9.2 g of the desired product.

13 C NMR (CDCl 3): 7.6; 18.8; 32.9; 35.7; 40.9; 51.3; 173.4; 210.5.

Preparation 5

(+/-) 1,5-heptanediol

Working in the same way as in the Preparation 1, and starting with 5.4 g of Methyl 5-oxoheptanoate, 4.2 g of the desired product

13 C NMR (CDCl 3): 9.9; 21.7; 30.0; 32.3; 36.2; 62.0; 72.8.

Preparation 6

(+/-) 1,5-octanediol

Working in the same way as for the Preparation 1, and starting from 20.0 g of Methyl 5-oxooctanoate, 16.9 g of the desired product

13 C NMR (CDCl 3): 14.0; 18.8; 21.7; 32.3; 36.7; 39.5; 62.0; 71.1.

Preparation 7

(+/-) 1,5-dichloroheptane

In a 100 ml reactor under the atmosphere of nitrogen, 20 ml of DMF was introduced. It was cooled to 0 ° C, then 5.6 ml of thionyl chloride was added in 10 minutes. It stirred thus 25 minutes, then a solution of 4.2 g of 1,5-heptanediol in 8 ml of DMF in 1.5 hours. Be It was stirred for 1 hour, then allowed to return to 20-25 ° C. It was then heated at 95 ° C for 45 minutes. It was cooled to 25 ° C and 200 ml of water was added. It was extracted three times with 80 ml of diethyl ether. The organic phases were washed twice with 80 ml of water, dried over potassium carbonate, filtered and dried concentrated with rotary evaporator. 5.0 g of the product were obtained wanted.

13 C NMR (CDCl 3): 10.9; 23.9; 31.4; 32.1; 37.2; 44.7; 65.2.

Preparation 8

(+/-) 1,5-dichlorooctane

Working in the same way as in the Preparation 7, and starting from 16.5 g of 1,5-octanediol, 11.8 g of the product were obtained wanted.

13 C NMR (CDCl 3): 13.5; 19.6; 23.8; 32.1; 37.7; 40.5; 44.7; 63.4.

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Preparation 9

2-pentin-1,5-diol

In a 250 ml three mouth reactor, successively introduced 26 ml of 3-butin-1-ol, 55 ml of 30% formaldehyde, 0.41 g of calcium carbonate and finally 4.9 g of cuprous hydroxide prepared just before use by the traditional method. It was stirred 10 minutes at 20-25 ° C, then 96 hours at 80 ° C. It cooled to 20-25 ° C, the solution obtained was filtered and concentrated. After distillation under vacuum, 15.3 g were recovered. of the product sought, (Eb_ {0,05} = 107-109 ° C).

13 C NMR (CDCl 3): 22.8; 50.6, 60.6; 79.9; 83.0

Preparation 10

Cis 2-penten-1,5-diol

In a 250 ml three mouth reactor, dissolved 15.1 g of 2-pentin-1,5-diol in 150 ml of ethyl acetate. Then 0.65 ml of chloroform then 0.71 g of palladium on barium sulfate (5%). Be stirred 5 minutes, then the assembly was purged with hydrogen and allowed to absorb an equivalent of hydrogen in 6 hours and a half to 20-25 ° C It was filtered over celite, washed with 50 ml. of ethyl acetate and concentrated. Thus 16.4 g of a oil corresponding to the product sought.

1 H NMR (CDCl 3): 2.35 (m, 2H); 3.61 (t, 2H, CH2); 4.1 (d, 2H, CH2); 4.15 (s, 2H, OH); 5.7 (m, 2H, CH = CH).

Preparation eleven

Cis 1,5-dibromo 2-pentene

In a three-mouth reactor of 100 ml, introduced 11 ml of tribromophosphine, cooled to 0 ° C then added 16.4 g of cis drop by drop 2-penten-1,5-diol in three hours. It was allowed to slowly return to 20-25 ° C and was  stirred for 15 hours. It was then cooled to 0 ° C, 30 ml were added of water in 30 minutes. It was stirred 5 minutes and then extracted by twice with 30 ml of dichloromethane. The organic phase was washed with 15 ml of water, dried over magnesium sulfate, filtered and concentrated. Thus 35 g of an oil corresponding to the expected product with sufficient purity to be used in later stages.

1 H NMR (CDCl 3): 2.55 (m, 2H, CH2); 3.43 (t, 2H, CH2 Br); 3.97 (d, 2H, BrCH2 C = C); 5.88 (m, 2H, CH = CH).

Preparation 12

6-chloro-1-phenyl-2-hexanone

In a 250 ml three-mouth reactor, under nitrogen atmosphere, 10 g of chloride were charged 5-Chlorovaleroyl in 50 ml of anhydrous THF. He cooled at -20 ° C and 1.06 g of copper chloride were added quickly (I). It was stirred 40 minutes, then added in 1.5 hours, 36 ml of a solution of 2M benzylmagnesium chloride in THF. Be stirred 1 hour at -20 ° C, then allowed to rise at 20 ° C in 1.5 hours. It was cooled to -10 ° C and 90 ml of 0.4 M hydrochloric acid was added. It was then stirred 20 minutes, then the aqueous phase was extracted by twice with 100 ml of MTBE. The organic phase was washed twice  with 50 ml of water, dried over magnesium sulfate, filtered and He concentrated. Thus 13.5 g of the product sought were recovered.

Preparation 13

(+/-) 6-chloro-1-phenyl-2-hexanol

In a 250 ml three mouth reactor, loaded 13.1 g of 6-chloro-1-phenyl-2-hexanone in 75 ml of ethanol. It was cooled to -5 ° C and a sodium borohydride solution (2.18 g) in 15 ml of water. Be stirred 2.5 hours at -5 ° C, allowed to return to 20 ° C in 1 hour, then cooled to -5 ° C. 110 ml of hydrochloric acid was then added 0.14 M. It was stirred 10 minutes, then extracted three times with 80 ml of methylene chloride. It was dried over magnesium sulfate, filtered and concentrated. 12.3 g of the product were thus recovered. expected.

Preparation 14

(+/-) 2,6-dichloro-1-phenylhexane

Working in the same way as in the Preparation 7 and starting from 12.3 g of 6-chloro-1-phenyl-2-hexanol and from 12.9 g of thionyl chloride, 13.3 g of the expected product.

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Preparation fifteen

(+/-) 1,5-dichloro-1-phenylpentane

Working in the same way as in preparations 12, 13 and 14 but using phenylmagnesium chloride instead of benzylmagnesium chloride, the product was obtained wanted.

Preparation 16

(+/-) 5-hexen-2-ol

In a 250 ml two-mouth reactor placed under argon containing 2 g of LiAlH4 and 130 ml of ethyl ether anhydrous, 10 g of at room temperature were added dropwise 5-hexenone diluted in 20 ml of ethyl ether anhydrous. The mixture was then refluxed for 2 hours. It was allowed to return to room temperature after cooling in ice bath 10 ml of ethanol was added dropwise then followed by 20 ml of distilled water. The agitation was cut to allow the white solid formed to deposit, then the supernatant was transferred to a settling ampoule. Be the phases were separated: the aqueous phase was extracted once with ether (5 ml) and the combined ether phases were washed with distilled water, They were dried over MgSO4 and concentrated. 9.5 g were obtained of product in the form of a clear oil.

1 H NMR (CDCl 3, δ ppm): 1.0 (d, CH 3); 1.4 (m, CH2 C = C); 2.0 (m, CH 2 C-O), 3.1 (s, OH); 3.6 (m, CH-O); 4.9 (m, CH2 = C); 5.7 (m, CH = C).

NMR - 13 C (CDCl 3, δ ppm): 23.0 (CH 3); 29.9 (CH 2 C = C); 38.0 (CH 2 C-O), 67.0 (CH-O); 114.3 (CH2 = C); 138.3 (m, CH = C).

Preparation 17

Δ5 -2-hexenyl phthalate

They were loaded into a 100 ml mouth reactor, 8 g (80 mmol) of 5-hexen-2-ol, 12.1 g (80 mmol) of phthalic anhydride and 40 ml of pyridine. The mixture is stirred at room temperature for 4 days. Then it was cast in a 500 ml flask filled up to 1/3 of crushed ice after acidified with ice cold concentrated HCl. The solution thus obtained It was extracted twice with frozen chloroform. The chloroform phases combined, washed three times with ice cold HCl (2N) and three times with a saturated solution of ice cold NaCl then dried over MgSO4 and concentrated. The concentrate dissolved in a slight excess of Na2CO3 solution (2N, 40 ml) frozen and This solution was extracted twice with ether. Then you acidified with ice cold HCl (2N) until the appearance of a cloudy white Persistent was then extracted with chloroform. Dissolution Organic was washed with a saturated solution of ice cold NaCl then It was dried over MgSO4 and concentrated. Thus 16 g of clear oil This oil, diluted in 10 ml of petroleum ether, is placed in a cold room (7 ° C) overnight with stirring soft. A very white precipitate of phthalate formed which was filtered and dried to give 14.3 g of residue (yield 72.3%).

Preparation 18

Resolution of Δ5 -2-hexenyl phthalate

In a 250 ml mouth reactor under a refrigerant, a mixture of 14 g of Δ5 -2-hexenyl phthalate, 18 g of anhydrous brucine and 200 ml of acetone was refluxed until obtaining a clear solution. It was allowed to cool to room temperature. A brucina salt precipitated and filtered, it dried and recrystallized once in acetone to give a mass of 13.6 g. To this salt dissolved hot in 700 ml of ethanol and 30 ml of HCl (2N), 100 ml of distilled water was added, then the solution It was cooled and extracted four times with ether. The ethereal phase is washed with HCl (2N) and with water, dried over MgSO4 and concentrated to give 5.5 g of a clear oil. The oil was hydrolyzed with 50 ml of a solution of NaOH (2N) in a one-mouth reactor 100 ml and was subjected to a steam drag. 2.2 g were obtained of clear oil characterized as (+) - 5-hexen-2-ol, [α] D = + 12.2 ° (c = 2.99; Et 2 O).

He (-) - 5-hexen-2-ol was obtained by concentrating the solution of the first filtrate around 1/3 of its volume and cooling in an ice bath. Salt Brucina thus precipitated was filtered, dried and treated as previously to give 2.5 g of product. [α] D = -11.1 ° ([C] = 2.5; Et2O).

1 H NMR (CDCl 3, δ ppm): 1.0 (d, CH 3); 1.4 (m, CH2 C = C); 2.0 (m, CH 2 C-O), 3.1 (s, OH); 3.6 (m, CH-O); 4.9 (m, CH2 = C); 5.7 (m, CH = C).

NMR - 13 C (CDCl 3, δ ppm): 23.0 (CH 3); 29.9 (CH 2 C = C); 38.0 (CH 2 C-O), 67.0 (CH-O); 114.3 (CH2 = C); 138.3 (m, CH = C).

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Preparation 19

(+) - 5-Chloro-1-Hexene

In a three-mouth reactor of 100 ml equipped with a refrigerant, a thermometer and an additive ampoule are placed 2.5 g (25 mmol) of (-) - 5-hexen-2-ol and 10 ml of tetrachloromethane to which was added dropwise a solution of 8 g of triphenylphosphine in 10 ml of dichloromethane. The mixture was stirred overnight at 25 ° C then cooled to temperature. Ambient and concentrated. The addition of pentane (20 ml) precipitated ? 3 PO that was filtered and the filtrate was concentrated. He concentrate was diluted in pentane and placed in ice bath for an hour later it was filtered again. Then the Filtrate passed through a silica gel with elution to pentane. After concentration, 1.3 g of product were obtained. He 1 H NMR analysis and the rotational power value indicate that the product obtained with configuration inversion is (+) - 5-Chloro-1-hexene.

[α] D = + 15.5 ° (c = 2.76; Et 2 O).

1 H NMR (CDCl 3, δ ppm): 1.50 (d, CH 3); 1.80 (m, CH2 C = C); 2.20 (m, CH 2 C-Cl), 4.0 (m, CH-Cl); 5.1 (m, CH2 = C); 5.7 (m, CH = C).

Preparation twenty

(+) - 5-Chloro-1-Hexanol

In a 50 ml three-mouth reactor under argon, 1 g of (+) - 5-Chloro-1-Hexene and 10 ml of anhydrous ether then the mixture was cooled in a bath of ice. 0.5 ml of BH 3: S (CH 3) 2 (10: 10.2 M) drop by drop and stirred one hour at room temperature. The reaction medium is then oxidized at 0-5 ° C with 4 ml of NaOH (3N) then with 8 ml of H2O2 (30%) and the mixture was stirred a Hour at room temperature. Then it was decanted and the phase aqueous was extracted three times with ether. The organic phases gathered washed with distilled water, dried over MgSO4 and dried concentrated to obtain 0.7 g (60.8%) of 5-chloro-1-hexanol.

[α] D = + 14.2 ° (c = 2.96; Et 2 O).

1 H NMR (CDCl 3, δ ppm): 1.45 (d, CH 3); 1.52 (m, 2CH2); 1.60-1.70 (m, CH2C = Cl), 3.16 (s, OH); 3.57 (t, CH 2 O); 4.1 (m, CH-Cl).

Preparation twenty-one

(+) - 1,5-dichlorohexane

The operating conditions are identical to the of the synthesis of 5-chloro-1-hexene using 400 mg (2.93 mmol) of (+) - 5-Chloro-1-hexanol, 3 ml of dichloromethane, 1g (3.81 mmol) of triphenylphosphine and 3 ml of tetrachloromethane. Finally 400 mg (85%) of (+) - 1,5-dichlorohexane.

[α] D = + 13.56 ° (c = 2.68; Et 2 O).

1 H NMR (CDCl 3, δ ppm): 1.50 (d, CH 3); 1.60-1.85 (m, 6H, CH2); 3.53 (t, 2H, CH2 -Cl), 4.1 (m, CH-Cl).

Example 1 (+/-) cis 2-methyl-1- (2-thienyl) -cyclohexane-carbonitrile

In a 6 l reactor, 430 g of potash was loaded (85%) in 1.7 l of DMF. The medium was then cooled to -20 ° C and added a solution of 191 g of 2-thienylacetonitrile in 0.7 l of DMF all refrigerating in order not to pass a temperature of -15 ° C. After this first phase, the addition was made immediately in 1 hour of a solution of 250 g of 1,5-dichlorohexane in 0.5 l of DMF leaving the temperature rise to -5 ° C. Finished these two additions, it He removed the cooling bath and allowed to trace in 40 minutes the temperature at 20-25 ° C. He let himself be stirred in these conditions 4.5 hours, then the DMF was removed under vacuum. Be recovered the medium obtained in 1.5 l of water and extracted by two times with 500 ml of heptane. The organic phase was washed twice with 500 ml of water, dried over magnesium sulfate, filtered and The solution obtained was concentrated. An oil was thus recovered greenish, which, after distillation under vacuum led to 267 g of a colorless oil that corresponds to the desired product. (Eb_ {2,1} = 90-100 ° C).

13 C NMR (CDCl 3): 18.0; 23.7; 25.4; 32.0; 41.2; 42.8; 48.1; 120.1; 124.4; 125.1; 126.6; 145.0.

Example 2 Acid (+/-) cis 2-methyl-1- (2-thienyl) -cyclohexane-carboxylic

In a 4 l reactor, 266 g were introduced cis-2-methyl-1- (2-thienyl) -cyclohexane-carbonitrile in 1 l of diethylene glycol. After 5 minutes of homogenization and Under good stirring, 2.4 kg of an aqueous solution was added of 60% potash. It was then stirred at 170 ° C for 24 hours. Be cooled to 20-25 ° C, then diluted with 1 l of water. It was poured onto 6.5 l of water and this medium was washed twice with 3 l of dichloromethane. Under good agitation, the medium by adding 2.5 l of concentrated hydrochloric acid. TO temperature below 30 ° C, this medium was extracted twice with 3 l of dichloromethane. The organic phase was reextracted by two times with 2 l of soda (containing the first 78 g of 99% soda and the second 2 g). The organic phase was separated. The phase was acidified. aqueous by adding 1 l hydrochloric acid (containing 230 ml of concentrated hydrochloric acid) and extracted twice with 2l of dichloromethane. The organic phase was washed with 2 l of water, treated with black and magnesium sulfate, filtered and concentrated.  The whitish solid obtained was crystallized from 1.65 l of heptane under agitation They were collected, after filtration and washing with heptane, 178 g of a white solid that corresponds to the product wanted. (m.p. = 109 ° C).

13 C NMR (CDCl 3): 16.1; 21.2; 22.1; 29.0; 31.5; 37.4; 52.5; 124.8; 1; 125.4; 126.5; 146.5; 180.9.

Example 3 Acid (+) cis 2-methyl-1- (2-thienyl) -cyclohexane-carboxylic

30 g of acid were dissolved respectively (+/-) cis-2-methyl-1- (2-thienyl) -cyclohexane-carboxylic and 43.4 g of quinine in 2.1 l of hot acetone. They mixed these two solutions and then let it slowly return to 20-25 ° C, and thus stirred 3 hours. Leaked and it washed with a little acetone. The solution was then concentrated. obtained. The salt obtained was recrystallized from 860 ml of acetone. Be released the acid from its isolated salt by an acid treatment 10% hydrochloric and by dichloromethane extraction. He concentrated the organic phase obtained, then dried over sulfate Magnesium and filtered. Thus, 8.8 g of the sought (+) acid were collected (mp = 109 ° C). [α] D 20 = + 70.95 ° (ethanol 0.8%).

NMR - 13 C (CDCl 3): identical to the compound of example 2.

Example 4 Acid (-) cis 2-methyl-1- (2-thienyl) -cyclohexane-carboxylic

The first filtrate obtained was concentrated dry during the preparation of example 3. The acid was released from its salt isolated by a treatment with 10% hydrochloric acid and by Extraction with dichloromethane. The organic phase was concentrated. obtained. 11.9 g of the released acid were dissolved respectively and  6.1 g of D (+) α-methyl-benzylamine in MTBE a solvent reflux. He let himself slowly return to 20-25 ° C, and thus stirred 3 hours. Leaked and it washed with a bit of MTBE. The salt obtained was recrystallized in a MTBE / EtOH mixture 7/3, filtered and the acid released as previously. 4.0 g of the desired (-) acid (p.f. = 109 ° C). [α] D 20 = -72.1 (0.8% ethanol).

This (-) acid can also be prepared reacting (+) - 1,5-dichlorohexane on 2-thienyl acetonitrile under the conditions of putting on  practice of example 1, then transforming the nitrile so formed, in acid under the conditions of implementation of the example 2.

NMR - 13 C (CDCl 3): identical to the compound of example 2.

Example 5 (+/-) cis 2-methyl-1- (2-thienyl) -cyclohexane-carboxylate of ethyl

In a 250 ml reactor, 2.5 g were dissolved acid (+/-) cis 2-methyl-1- (2-thienyl) -cyclohexane-carboxylic in 60 ml of toluene. Then 3 ml of chloride were added. thionyl in 15 minutes. It was allowed to homogenize 5 minutes, then it was progressively led to reflux controlling detachment soda (1 hour). It was stirred at reflux for 2 hours. It distilled then excess thionyl chloride to obtain vapors at 108-110 ° C, then toluene. 60 ml of ethanol and the rest of toluene was removed by distilling the azeotropic toluene / ethanol until obtaining vapors at 77-78 ° C. At 20-25 ° C, it was added in 20 minutes a solution of 1.5 g of sodium ethanolate in 50 ml of ethanol It was allowed to homogenize 5 minutes, then it was taken to reflux for 15 hours. The ethanol was then taken, then recovered in 100 ml of water, extracted three times with 50 ml of ether. The organic phases were washed with 100 ml of water, dried over magnesium sulfate, filtered and concentrated with evaporator rotary. Thus 2.36 g of an oil corresponding to the desired product

13 C NMR (CDCl 3): 12.3; 13.9; 21.8; 22.4; 29.3; 32.1; 38.1; 52.7; 60.5; 123.8; 124.8; 126.2; 147.6; 174.0.

Example 6 (+/-) trans 2-methyl-1- (2-thienyl) -cyclohexane-carboxylate of ethyl

Working in the same way as in example 1 but starting from 3 g of 2-thiophene ethyl acetate instead of 2-thienyl acetonitrile, 1.3 were obtained g of the compound sought. It was identified by comparing the structures of the compound obtained by basic hydrolysis of the latter with the structures of the compound of example 2.

Example 7 Acid (-) cis 2-methyl-1- (2-thienyl) -cyclohexane-carboxylic

In a three-mouth reactor of 100 ml, successively introduced 50 ml phosphate buffer (pH = 7), 0.15 ml of a 1g solution of (+/-) cis 2-methyl-1- (2-thienyl) -cyclohexane-carboxylate of ethyl in 2-propanol and 0.46 mg of Porcine Liver Esterase Crude. Then the whole group was stirred vigorously 72 hours at 40 ° C. It was cooled to 20-25 ° C, the medium was filtered on Sephadex the medium was then made alkaline by the addition of 20 ml. of 5% soda. It was extracted three times with 100 ml of MTBE. Be washed the organic phase with 100 ml of water. The aqueous phases are gathered then acidified by adding 26 ml of acid 5% hydrochloric. It was extracted three times with 100 ml of MTBE. Be washed the whole organic phases with 100 ml of water, dried over magnesium sulfate, filtered and concentrated to recover 0.4 g of the compound sought.

NMR - 13 C (CDCl 3): identical to the compound of example 4.

Example 8 Acid (+) cis 2-methyl-1- (2-thienyl) -cyclohexane-carboxylic

The first MTBE phase obtained in the Preparation of Example 7, over magnesium sulfate, was filtered and He concentrated. The oil obtained was then recovered with 2 ml of ethylene glycol It was homogenized then 4.8 g of potash was added 60% aqueous. It was then stirred 17 hours at 170 ° C. It cooled to 20-25 ° C, 15 ml of water was added. He washed this half twice with 10 ml dichloromethane. It was acidified by addition of 5 ml of concentrated hydrochloric acid. It was extracted by twice with 10 ml of dichloromethane. The set of the washes was washed organic phases with 10 ml of water, dried over sulfate magnesium, filtered and concentrated to recover 0.45 g of compound sought.

NMR - 13 C (CDCl 3): identical to the compound of example 3.

Example 9 (+/-) cis 2-methyl-1- (2-thienyl) -cyclohexane-carboxamide

In a 2 l reactor under nitrogen atmosphere, 59 g of cis acid were dissolved 2-methyl-1- (2-thienyl) -cyclohexane-carboxylic in 600 ml of toluene. Then 71 ml of chloride were added. thionyl in 15 minutes. It was allowed to homogenize 5 minutes, then it was progressively led to reflux controlling detachment gas (4 hours). The excess chloride was then distilled off. thienyl until obtaining vapors at 108-110 ° C. It was cooled under these conditions at 10 ° C, then allowed to bubble Ammonia with a fairly large flow rate without cooling. He left the temperature rise to 65 ° C then descend to 20-30 ° C After the absorption of ammonium, it was stirred 1 hour, then the medium was degassed by bubbling nitrogen and 600 ml of water was added. The two phases were decanted, and re-extracted the aqueous phase with 300 ml of toluene. He washed the whole of the organic phases twice with 250 ml of water and concentrated the middle. The brownish solid obtained was crystallized from 360 ml of heptane to lead to 52 g of the product sought (m.p. = 100 ° C).

13 C NMR (CDCl 3): 15.8; 20.5; 21.9; 29.0; 30.2; 36.2; 52.4; 124.3; 124.8; 126.9; 148.8; 177.1.

Example 10 (+/-) cis 2-methyl-1- (2-thienyl) -cyclohexylamide

In a reactor of three mouths of 1 l, they dissolved 60 g potash in 240 ml of water. The whole cooled to 0 ° C 7 ml of bromine was added at once. It was allowed to homogenize 10 minutes later, a quick addition (7 minutes) was added 20.5 g cis solution 2-methyl-1- (2-thienyl) -cyclohexane-carboxamide and 0.5 g of tetrabutylammonium hydrogen sulfate in 220 ml of dichloromethane It was stirred for 1 hour, then the two were decanted phases The organic phase was washed with 100 ml of water and concentrated the reaction medium in order to isolate the isocyanate intermediate.

In a second reactor with three 1 l nozzles, they dissolved 71 g of soda (99%) in 170 ml of water. It cooled set at 20-25 ° C. It was added quickly (4 minutes) a solution of 23.2 g of intermediate isocyanate and 0.5 g of tetrabutylammonium hydrogen sulfate in 210 ml of MTBE. Be It was stirred for 7 hours, then the two phases were decanted. It was extracted the aqueous phase with 170 ml of MTBE. The organic phase was washed with 70 ml of water The organic phase was extracted twice with 200 ml of acidified water (containing the first 100 ml of acid 5% hydrochloric and the second 1 ml). The aqueous phase was washed with 100 ml of MTBE. It was made alkaline by the addition of 170 ml of 5% soda and It was extracted twice with 200 ml of MTBE. Phase was washed organic with 100 ml of water, dried over magnesium sulfate, filtered and concentrated. 17.2 g of an oil were collected and corresponds to the desired amine.

13 C NMR (CDCl 3): 15.9; 22.1; 25.9; 30.2; 41.7; 43.7; 56.9; 121.1; 122.5; 126.5; 157.4.

Example 11 (+) cis 2-methyl-1- (2-thienyl) -cyclohexylamide

3.0 g of (+/-) cis were dissolved 2-methyl-1- (2-thienyl) -cyclohexanamine  and 2.3 g of (-) tartaric acid in the minimum 95% aqueous ethanol hot. It was stirred for 12 hours at 20-25 ° C. Be filtered washing with a little ethanol and heptane. Recrystallized with four repetitions the crystals obtained in ethanol 95. It The solid was recovered in water and the amine was released by the addition of soda. at 5% The amine was then extracted with ethyl ether, dried with magnesium sulfate and concentrated. 0.25 g of the product sought. [α] D 20 = +14.7 (methanol, 2%).

NMR - 13 C (CDCl 3): identical to the compound of example 10.

Example 12 (-) cis 2-methyl-1- (2-thienyl) -cyclohexylamine

The different filtrates were concentrated obtained during the preparation of example 11. The amine was released according to the same protocol as before. It crystallized then with the help of (+) tartaric acid in the minimum 95% ethanol in hot. It was stirred for 12 hours at 20-25 ° C. Leaked  washing with a little ethanol and petroleum ether. Be recrystallized with three repetitions the crystals obtained in 95% ethanol. The solid was recovered in water and the amine was released by adding 5% soda. The amine was then extracted with ether ethyl, dried over magnesium sulfate and concentrated. Be thus obtained 0.31 g of the product sought. [α] D 20 = -15.5 (methanol, 2%).

NMR - 13 C (CDCl 3): identical to the compound of example 10.

Example 13 (+/-) cis 2-methyl-1- (2-thienyl) -cyclohexyl-piperidine

In a 250 ml three mouth reactor, dissolved 5.7 g of cis 2-methyl-1- (2-thienyl) -cyclohexanamine and 5 ml of 1,5-dibromopentane in 60 ml of sulfolane. After 5 minutes of homogenization, 11.7 were added suddenly ml of potassium carbonate and 2.1 g of sodium iodide. Left homogenize again 5 minutes later it was brought to 80 ° C for 20 hours. The whole was cooled to 25-30 ° C. It was treated by adding 300 ml of water and 100 ml of MTBE. They opted for Two phases. The aqueous phase was reextracted with 150 ml of MTBE. He washed the organic phase with 100 ml of water. The organic phase was extracted by twice with 150 ml of acidified water (containing the first 40 ml of 5% hydrochloric acid and the second 10 ml). They washed Acidic aqueous phases combined with 100 ml of MTBE and the organic phases the aqueous phases were alkalized by the addition of 70 ml of 5% soda and extracted twice with 100 ml of MTBE. The organic extraction phase was washed with 50 ml of water, treated with black and with magnesium sulfate, it was filtered over clarcel and concentrated. 7.5 g of a residue that crystallized was collected. in 150 ml of methanol. 5.9 g were then recovered by filtration. of a white solid that corresponds to the molecule sought (p.f. = 81-82 ° C).

13 C NMR (CDCl 3): 14.0; 19.4; 23.1; 25.1; 27.0; 29.5; 30.1; 33.9; 46.0; 52.7; 122.1; 124.0; 125.9; 144.7.

Example 14 (+/-) cis hydrochloride 2-methyl-1- (2-thienyl) -cyclohexyl-piperidinium

In a 250 ml three mouth reactor, introduced 57 ml of a 1 M hydrochloric acid solution in MTBE Under good stirring and under nitrogen atmosphere, was added quite quickly a solution of 5 g of (+/-) cis 2-methyl-1- (2-thienyl) -cyclohexyl-piperidine in 45 ml of MTBE. After the addition was finished, it was allowed to stir 3 hours It was then filtered and dried over 1 torr at 45 ° C. They were collected like this 5.4 g of the product sought (m.p. = 230-1 ° C).

13 C NMR (CDCl 3): 15.8; 17.8; 22.1; 22.3; 22.5; 22.6; 26.5; 30.2; 35.4; 46.7; 48.9; 72.9; 127.2; 127.6; 130.1; 136.9.

Example 15 (+) Cis hydrochloride 2-methyl-1- (2-thienyl) -cyclohexyl-piperidinium 15 a. Chemical resolution

17.53 g of (+/-) cis 2-methyl-1- (2-thienyl) -cyclohexyl-piperidine and 12.7 g of acid were dissolved respectively
(-) di O, O'-toluoyl tartaric in the minimum hot isopropanol. These two solutions were mixed and then allowed to slowly return to 20-25 ° C, and stirred for 4 hours. It was filtered by washing with a little isopropanol and heptane. The solid was recovered in water and the mine was released by adding 5% soda. The amine was then extracted with MTBE, dried over magnesium sulfate and concentrated. The proportion of enantiomer enrichment (+) was analyzed by HPLC on chiral column and the crystallization operation was repeated three additional times by adding the amount of (-) di-O, O'-toluyltartaric acid in stoichiometric ratio above. In this manner, 3.2 g of the amine (+) was collected with an enantiomeric excess greater than 99%. The hydrochlorination of the amine was carried out identically to that described during the preparation of example 14, and allowed to obtain 3.6 g of the product sought (mp = 230-1 ° C).

The NMR is identical to the product of the example 14.

15 b. Chemical synthesis

Practicing as indicated during the preparations of examples 9,10,13 and 14 and using 23.2 g of acid (+) cis 2-methyl-1- (2-thienyl) -cyclohexane-carboxylic acid, 18.2 g of sought hydrochloride (+) were obtained (p. f. = 230-1ºC).

The NMR is identical to the product of the example 14.

Example 16 (-) cis hydrochloride 2-methyl-1- (2-thienyl) -cyclohexyl-piperidinium 16 a. Chemical resolution

The first filtrate obtained was concentrated during the preparation of example 15 a, and the operation of crystallization with the help of acid (+) di-O, O'-toluyltartaric in the same conditions as before, three times in a row. After from the hydrochlorization, 3.7 g of the product sought were isolated (e.g. F. = 230-1 ° C).

The NMR is identical to the product of the example 14.

16 b. Chemical synthesis

Practicing as indicated during the preparations of examples 9,10,13 and 14 and using 11.25 g of acid (-) cis 2-methyl-1- (2-thienyl) -cyclohexane-carboxylic acid, 8.1 g of the desired (-) hydrochloride (p. f. = 230-1ºC).

The NMR is identical to the product of the example 14.

[α] D 24 = -32.3.

Example 17 N - [α-methyl- ((S) -phenylmethyl)] cis 2-methyl-1- (2-thienyl) -cyclohexane-carboxamide

In a 100 ml reactor under the atmosphere of nitrogen, 2.0 g of acid dissolved cis-2-methyl-1- (2-thienyl) -cyclohexane-carboxylic in 20 ml of toluene. Then 1.3 ml of chloride were added. Thionyl in 5 minutes. It was allowed to homogenize 5 minutes, then it was progressively led to reflux controlling detachment soda (1 hour). The excess chloride was then distilled off. thionyl until obtaining vapors at 108-110 ° C. It was cooled to 20 ° C, then a solution of 2.55 g of α-methyl- (S) -phenylmethylamine in 40 ml of toluene without cooling in 15 minutes. He let the temperature up to 40 ° C then dropped to 20-30 ° C. It was stirred at 25 ° C for 2 hours, then 40 ml of Water. The two phases were decanted. The organic phase was washed by two times with 40 ml of water, 40 ml of hydrochloric acid and 40 ml of water. After concentration of the medium, the solid residue obtained it was crystallized from 40 ml of pentane to lead to 2.4 g of product sought.

CCM (SiO2 60F254, eluent hexane / ether 5/5 diethyl, UV revelation, Rf = 0.66).

Example 18 (+/-) cis 2-methyl-1- (3-thienyl) -cyclohexane-carbonitrile

In a 500 ml three-mouth reactor, they put 43 g of potash in 160 ml of DMF. It cooled then the medium at -10 ° C and a solution of 17.6 g of 3-thienylacetonitrile in 40 ml of DMF in 30 minutes all this keeping the temperature at -10ºC. It stirred like that 20 minutes Then the solution of 24.7 g of 1,5-dichlorohexane in 40 ml of DMF in 30 minutes at -10 ° C. It was stirred for 15 minutes, allowed to return to 20-25 ° C in 1.5 hours. It was then stirred for 18 hours at 25 ° C, then 4 hours at 60 ° C. It was allowed to cool to 20-25 ° C after having removed the DMF under vacuum, then recovered in 1l of water. It was extracted with 600 ml after with 400 ml of heptane. The organic phase was washed with 400 ml of water then with 400 ml of a solution of sodium chloride. Dried up over magnesium sulfate, the solution was filtered and concentrated obtained. After distillation under vacuum, 15.2 g of  a colorless oil corresponding to the desired product (Eb 0.08) = 114-120 ° C).

13 C NMR (CDCl 3): 17.9; 23.5; 25.2; 34.7; 39.1; 40.7; 47.8; 121.2; 121.3; 124.7; 126.6; 142.1.

Example 19 Acid (+/-) cis 2-methyl-1- (3-thienyl) -cyclohexane-carboxylic acid

Starting from 15.0 g of (+/-) cis 2-methyl-1- (3-thienyl) -cyclohexane-carbonitrile and proceeding in the same way as described in the preparation from example 2, were obtained after crystallization in 4 heptane volumes, 11.6 g of the compound sought.

CCM (SiO2 60F254, eluent diethyl ether, UV revelation, Rf = 0.7).

Example 20 (+/-) cis 2-methyl-1- (3-thienyl) -cyclohexane-carboxamide

Starting from 11.6 g of acid (+/-) cis 2-methyl-1- (3-thienyl) -cyclohexane-carboxylic acid and proceeding in the same way as described in the preparation from example 9, were obtained after crystallization in 5 volumes of heptane, 12.0 g of the compound sought.

13 C NMR (CDCl 3): 16.0; 21.2; 22.1; 29.1; 30.8; 35.6; 52.1; 121.4; 126.1; 126.9; 145.1; 177.5.

Example 21 (+/-) cis 2-methyl-1- (3-thienyl) -cyclohexanamide

Starting from 11.6 g of acid (+/-) cis 2-methyl-1- (3-thienyl) -cyclohexane-carboxamide and proceeding in the same way as described in the preparation from example 10, 6.9 g of an oil were obtained practically colorless corresponding to the compound sought.

13 C NMR (CDCl 3): 15.2; 15.9; 21.9; 26.1; 30.1; 40.3; 41.8; 56.3; 118.9; 125.2; 125.5; 152.4.

Example 22 (+/-) cis 2-methyl-1- (3-thienyl) -cyclohexyl-piperidine

Starting from 5.7 g of (+/-) cis 2-methyl-1- (3-thienyl) -cyclohexanamide and proceeding in the same way as described in the preparation from example 13, were obtained after crystallization in 14 volumes of methanol, 5.9 g of the compound sought.

13 C NMR (CDCl 3): 13.7; 19.6; 23.0; 25.1; 27.0; 28.8; 29.3; 32.7; 46.0; 62.2; 120.8; 123.1; 127.8; 141.1.

Example 23 (+/-) cis hydrochloride 2-methyl-1- (3-thienyl) -cyclohexyl-piperidinium

Starting from 0.7 g of (+/-) cis 2-methyl-1- (3-thienyl) -cyclohexyl-piperidine and proceeding in the same way as described in the preparation from example 14, 0.62 g of the hydrochloride sought (p. f.  = 230 ° C).

13 C NMR (CDCl 3): 15.5; 18.1; 22.1; 22.3; 22.6; 25.8; 29.9; 33.5; 46.6; 48.8; 72.0; 126.5; 126.6; 134.2.

Example 24 (+/-) [cis 2-methyl-1- (3-thienyl) cyclohexyl] 1,2,3,6-tetrahydropyridine

Starting from 11.5 g of (+/-) cis 2-methyl-1- (2-thienyl) -cyclohexanamine and 35 g of cis-1,5-dibromo pent-2-eno and proceeding from it such as that described in the preparation of example 13, is recovered 15.2 g of a beige solid that was purified by Chromatography on 590 g of alumina (Merck 90) (eluent heptane). Thus, 4.81 g of the compound sought was obtained.

13 C NMR (CDCl 3): 14.1; 19.4; 23.0; 27.3; 29.4; 34.4; 42.1; 44.5; 62.9; 122.6; 124.5; 124.8; 126.0; 126.5; 143.6.

Example 25 Hydrochloride (+/-) [cis 2-methyl-1- (2-thienyl) cyclohexyl] 1,2,3,6-tetrahydropyridinium

Starting from 0.24 g of (+/-) cis 2-methyl-1- (3-thienyl) -cyclohexyl  1,2,3,6-tetrahydropyridine and coming from the same way as described in the preparation of example 14, recovered 0.2 g of the compound sought (p. f. = 182-184 ° C).

Example 26 (+/-) cis 2-ethyl-1- (2-thienyl) -cyclohexane-carbonitrile

Working in the same way as for the Preparation of Example 1 but starting from 4.8 g of 1,5-dichloroheptane instead of 1,5-dichlorohexane, 2.8 g of the product were obtained wanted.

13 C NMR (CDCl 3): 10.1; 22.3; 23.1; 23.9; 26.8; 41.4; 46.9; 47.9; 118.9; 123.0; 123.7; 125.0; 143.8.

Example 27 (+/-) cis 2-Pripyl-1- (2-thienyl) -cyclohexane-carbonitrile

Working in the same way as in the example 1 but starting with 5.1 g of 1,5-dichloroctane instead of 1,5-dichlorohexane, 3.3 g of the desired compound.

13 C NMR (CDCl 3): 13.9; 23.8; 24.9; 25.4; 28.9; 33.9; 42.0; 47.1; 47.8; 120.5; 124.4; 125.2; 126.4; 145.3.

Example 28 (+/-) cis 2-Benzyl-1- (2-thienyl) -cyclohexane-carbonitrile

Working in the same way as in example 1 but using 2,6-dichloro-1-phenylhexane instead of 1,5-dichlorohexane, the product was obtained  wanted.

Example 29 (+/-) cis 2-phenyl-1- (2-thienyl) -cyclohexane-carbonitrile

Working in the same way as in example 1 but using 1,5-dichloro-1-phenylpentane instead of 1,5-dichlorohexane, the product was obtained  wanted.

Using the indicated procedure previously, you can also prepare the following products:

TABLE 1

7

8

Claims (6)

1. Procedure for preparing compounds of general formula I 9 in racemic form, of diestereoisomers or enantiomers, in the which: R represents the cyano radical or -C (O) A in which A represents a radical of formula OR 1 or NR 2 R 3 and R 1, R 2 and R 3 independently represent a hydrogen atom or a group alkyl optionally substituted with aryl; R 'represents the radical 2-thienyl or 3-thienyl; R '' represents an alkyl radical if any substituted with aryl; or an aryl radical, as well as the salts of these products, characterized in that a product of general formula 1 is reacted 1R'CH_ {R} in which R and R 'have the meanings indicated above, with a product of formula general 2 10 in which Y and Y 'represent, independently, removable groups and R '' has the significance indicated above, to give a product of formula I. 2. Process according to claim 1, for the preparation of compounds of general formula I in the form of an enantiomer, characterized in that a compound of formula 2 is reacted in the form of an enantiomer. 3. Compounds of formula 2 as defined in claim 1, in racemic or enantiomeric form. 4. Compounds of general formula I: eleven in racemic form, of diestereoisomers or enantiomers, in the which: R represents the cyano radical; a radical of formula -C (O) A in which A represents a radical of formula OR 1 or NR 2 R 3 in which R 1, R 2 and R 3 independently represent a hydrogen atom or a alkyl group optionally substituted with aryl; R 'represents the radical 2-thienyl or 3-thienyl; R '' represents an alkyl radical if any substituted with aryl; or an aryl radical; as well as the salts of these products. 5. Compounds of general formula I as is defined in claim 4, wherein R represents the cyano radical; a radical of formula -C (O) A in which A represents a radical of formula OR 1 or NR 2 R 3, and R 1, R 2 and R 3 independently represent a hydrogen atom, a radical alkyl containing 1 to 6 carbon atoms and eventually substituted with phenyl; R 'represents the radical 2-thienyl or 3-thienyl; R '' represents an alkyl radical containing 1 to 6 carbon atoms and optionally substituted with phenyl; or a phenyl radical. 6. Compounds of general formula I as is defined in one of claims 4 or 5, in racemic form, of diestereoisomers or enantiomers, and that respond to the formulas following: - 2-methyl-1- (2-thienyl) -cyclohexane-carbonitrile; - acid 2-methyl-1- (2-thienyl) -cyclohexane-carboxylic acid; - 2-methyl-1- (2-thienyl) -cyclohexane-carboxylate of ethyl; - 2-methyl-1- (2-thienyl) -cyclohexane-carboxamide; - N - [α-methyl - ((S) -phenylmethyl)] 2-methyl-1- (2-thienyl) -cyclohexane-carboxamide; - 2-methyl-1- (3-thienyl) -cyclohexane-carbonitrile; - acid 2-methyl-1- (3-thienyl) -cyclohexane-carboxylic acid; - 2-methyl-1- (3-thienyl) -cyclohexane-carboxamide; - 2-ethyl-1- (2-thienyl) -cyclohexane-carbonitrile; - 2-propyl-1- (2-thienyl) -cyclohexane-carbonitrile; - 2-benzyl-1- (2-thienyl) -cyclohexane-carbonitrile; - 2-phenyl-1- (2-thienyl) -cyclohexane-carbonitrile.